Benzazepine derivatives and uses thereof

ABSTRACT

Compounds of the formula: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts, solvates or prodrugs thereof,
 
wherein Ar, R 1  and R 2  are defined herein. Also provided are pharmaceutical compositions, methods of preparing the compounds, and method of using the compounds for treatment of monoamine reuptake inhibitor-mediated diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is entitled to the benefit of provisional patentapplication Ser. No. 60/809,565 filed May 31, 2006, the disclosure ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to benzazepine compounds and methods for usingthe same. In particular, compounds of the present invention are usefulfor treatment of diseases associated with monoamine reuptake inhibitors.

BACKGROUND OF THE INVENTION

Monoamine deficiency has been long been linked to depressive, anxiolyticand other disorders (see, e.g.: Chamey et al., J. Clin. Psychiatry(1998) 59, 1-14; Delgado et al., J. Clin. Psychiatry (2000) 67, 7-11;Resser et al., Depress. Anxiety (2000) 12 (Suppl 1) 2-19; and Hirschfeldet al., J. Clin. Psychiatry (2000) 61, 4-6. In particular, serotonin(5-hydroxytryptamine) and norepinephrine are recognized as keymodulatory neurotransmitters that play an important role in moodregulation. Selective serotonin reuptake inhibitors (SSRIs) such asfluoxetine, sertraline, paroxetine, fluvoxamine, citalopram andescitalopram have provided treatments for depressive disorders (Masandet al., Harv. Rev. Psychiatry (1999) 7, 69-84). Noradrenaline ornorepinephrine reuptake inhibitors such as reboxetine, atomoxetine,desipramine and nortryptyline have provided effective treatments fordepressive, attention deficit and hyperactivity disorders (Scates etal., Ann. Pharmacother. (2000) 34, 1302-1312; Tatsumi et al., Eur. J.Pharmacol. (1997) 340, 249-258).

Enhancement of serotonin and norepinephrine neurotransmission isrecognized to be synergistic in the pharmacotherapy of depressive andanxiolytic disorders, in comparison with enhancement of only serotoninor norepinephrine neurotransmission alone (Thase et al., Br. J.Psychiatry (2001) 178, 234, 241; Tran et al., J. Clin.Psychopharmacology (2003) 23, 78-86). Dual reuptake inhibitors of bothserotonin and norepinephrine, such as duloxetine, milnacipran andvenlafaxine are currently under development for treatment of depressiveand anxiolytic disorders (Mallinckrodt et al., J. Clin. Psychiatry(2003) 5(1) 19-28; Bymaster et al., Expert Opin. Investig. Drugs (2003)12(4) 531-543). Dual reuptake inhibitors of serotonin and norepinephrinealso offer potential treatments for schizophrenia and other psychoses,dyskinesias, drug addition, cognitive disorders, Alzheimer's disease,obsessive-compulsive behaviour, attention deficit disorders, panicattacks, social phobias, eating disorders such as obesity, anorexia,bulimia and “binge-eating”, stress, hyperglycaemia, hyperlipidemia,non-insulin-dependent diabetes, seizure disorders such as epilepsy, andtreatment of conditions associated with neurological damage resultingfrom stroke, brain trauma, cerebral ischaemia, head injury andhemorrhage. Dual reuptake inhibitors of serotonin and norepinephrinealso offer potential treatments for disorders and disease states of theurinary tract, and for pain and inflammation.

More recently, “triple reuptake” inhibitors (“broad-spectrumantidepressants” which inhibit the reuptake of norepinephrine,serotonin, and dopamine, have been recognized as useful for thetreatment of depression and other CNS indications (Beer et al., J.Clinical Pharmacology (2004) 44:1360-1367; Skolnick et al., Eur J.Pharmacol. (2003) February 14;461(2-3):99-104.

There is accordingly a need for compounds that are effective asserotonin reuptake inhibitors, norepinephrine reuptake inhibitors,dopamine reuptake inhibitors, and/or dual reuptake inhibitors ofserotonin, norepinephrine and/or dopamine, or triple reuptake inhibitorsof norepinephrine, serotonin, and dopamine, as well as methods of makingand using such compounds in the treatment of depressive, anxiolytic,genitourinary, pain, and other disorders. The present inventionsatisfies these needs.

SUMMARY OF THE INVENTION

One aspect of the invention provides compounds of formula I:

wherein:

-   Ar is optionally substituted indolyl;-   R¹ is:

hydrogen; or

C₁₋₆alkyl; and

-   R² is:

hydrogen;

C₁₋₆alkyl;

C₁₋₆alkoxy;

halo;

halo-C₁₋₆alkyl;

hetero-C₁₋₆alkyl;

C₁₋₆alkylsulfonyl;

cyano;

amino;

C₁₋₆alkylamino;

di-C₁₋₆alkylamino;

heterocyclyl selected from piperazinyl, piperidinyl, pyrrolidinyl,morpholinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl,each optionally substituted;

heterocyclyl-C₁₋₆alkyl selected from piperazinyl-C₁₋₆alkyl,piperidinyl-C₁₋₆alkyl, pyrrolidinyl-C₁₋₆alkyl, morpholinyl-C₁₋₆alkyl,thiomorpholinyl-C₁₋₆alkyl, tetrahydropyranyl-C₁₋₆alkyl andtetrahydrofuranyl-C₁₋₆alkyl, the heterocyclyl portion of each optionallysubstituted;

—(CH₂)_(m)—C(O)—NR^(a)R^(b);

—(CH₂)_(m)—SO₂—NR^(a)R^(b);

—(CH₂)_(m)—C(O)—OR^(c);

—NR^(d)—C(O)—R^(e);

—NR^(d)—SO₂—R^(e);

—O—C(O)—R^(e);

—O—C(O)—NR^(a)R^(b);

—NR^(d)—C(O)—NR^(a)R^(b); or

—NR^(d)—C(O)—OR^(c);

-   -   wherein m is 0 or 1 and R^(a), R^(b), R^(c), R^(d) and R^(e)        each independently is hydrogen or C₁₋₆alkyl.

Also provided are methods of making the subject compounds,pharmaceutical compositions comprising the subject compounds, andmethods of using the subject compounds for treatment of monoaminereuptake inhibitor-mediated diseases.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Agonist” refers to a compound that enhances the activity of anothercompound or receptor site.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.“Branched alkyl” means isopropyl, isobutyl, tert-butyl,

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” means a moiety of the formula —OR, wherein R is an alkyl moietyas defined herein. Examples of alkoxy moieties include, but are notlimited to, methoxy, ethoxy, isopropoxy, tert-butoxy and the like.

“Alkoxyalkyl” means a moiety of the formula —R′—R″, where R′ is alkyleneand R″ is alkoxy as defined herein. Exemplary alkoxyalkyl groupsinclude, by way of example, 2-methoxyethyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkylcarbonyl” means a moiety of the formula —R′—R″, where R′ is oxoand R″ is alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —R′—R″, where R′ is —SO₂—and R″ is alkyl as defined herein.

“Alkylsulfonylalkyl” means a moiety of the formula R^(a)—SO₂—R^(b)—,where R^(a) is alkyl and R^(b) is alkylene as defined herein. Exemplaryalkylsulfonylalkyl groups include, by way of example,3-methanesulfonylpropyl, 2-methanesulfonylethyl, 2-methanesulfonylpropy,and the like.

“Alkylsulfonyloxy” means a moiety of the formula R^(a)—SO₂—O—, whereR^(a) is alkyl as defined herein.

“Antagonist” refers to a compound that diminishes or prevents the actionof another compound or receptor site.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, optionally substituted phenyl,naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl,oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl,diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl,benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl,benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl,benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and thelike, including partially hydrogenated derivatives thereof.

“Aryloxy” means a moiety of the formula —OR, wherein R is an aryl moietyas defined herein.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Aralkoxy” means a moiety of the formula —OR, wherein R is an aralkylmoiety as defined herein.

“Cyanoalkyl” means a moiety of the formula —R′—R″, where R′ is alkyleneas defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Cycloalkyl can optionally be substitutedwith one or more substituents, wherein each substituent is independentlyhydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, ordialkylamino, unless otherwise specifically indicated. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like,including partially unsaturated derivatives thereof.

“Cycloalkyloxy” and “cycloalkoxy”, which may be used interchangeably,mean a group of the formula —OR wherein R is cycloalkyl as definedherein. Exemplary cycloalkyloxy include cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and the like.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Cycloalkylalkyloxy” and “cycloalkylalkoxy”, which may be usedinterchangeably, mean a group of the formula —OR wherein R iscycloalkylalkyl as defined herein. Exemplary cycloalkyloxy includecyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy,cyclohexylmethoxy and the like.

“Heteroalkyl” means an alkyl radical as defined herein, including abranched C₄-C₇-alkyl, wherein one, two or three hydrogen atoms have beenreplaced with a substituent independently selected from the groupconsisting of —OR^(a), —NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is aninteger from 0 to 2), with the understanding that the point ofattachment of the heteroalkyl radical is through a carbon atom, whereinR^(a) is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R^(b)and R^(c) are independently of each other hydrogen, acyl, alkyl,cycloalkyl, or cycloalkylalkyl; and when n is 0, R^(d) is hydrogen,alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R^(d) isalkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, ordialkylamino. Representative examples include, but are not limited to,2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl,2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl,3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl,aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic, bicyclic or tricyclic radical of 5 to12 ring atoms having at least one aromatic ring containing one, two, orthree ring heteroatoms selected from N, O, or S, the remaining ringatoms being C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, thienyl, thiophenyl, furanyl, pyranyl,pyridinyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl,benzofuryl, benzofuranyl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzoxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, including partially hydrogenated derivatives thereof.

“Heteroarylalkyl” and “heteroaralkyl”, which may be usedinterchangeably, mean a radical-R^(a)R^(b) where R^(a) is an alkylenegroup and R^(b) is a heteroaryl group as defined herein

The terms “halo” and “halogen”, which may be used interchangeably, referto a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. Examples of haloalkoxy moieties include, butare not limited to, trifluoromethoxy, difluoromethoxy,2,2,2-trifluoroethoxy, and the like.

“Hydroxyalkyl” refers to a subset of heteroalkyl and refers inparticular to an alkyl moiety as defined herein that is substituted withone or more, preferably one, two or three hydroxy groups, provided thatthe same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl,pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl,tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

“Optionally substituted”, when used in association with “aryl”, phenyl”,“heteroaryl” (including indolyl such as indol-1-yl, indol-2-yl andindol-3-yl, 2,3-dihydroindolyl such as 2,3-dihydroindol-1-yl,2,3-dihydroindol-2-yl and 2,3-dihydroindol-3-yl, indazolyl such asindazol-1-yl, indazol-2-yl and indazol-3-yl, benzimidazolyl such asbenzimidazol-1-yl and benzimidazol-2-yl, benzofuranyl such asbenzofuran-2-yl and benzofuran-3-yl, benzothiophenyl such asbenzothiophen-2-yl and benzothiophen-3-yl, benzoxazol-2-yl,benzothiazol-2-yl, thienyl, furanyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyrazolyl and quinolinyl)” or “heterocyclyl”, means an aryl,phenyl, heteroaryl or heterocyclyl which is optionally substitutedindependently with one to four substituents, preferably one or twosubstituents selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl,haloalkoxy, cyano, nitro, heteroalkyl, amino, acylamino,mono-alkylamino, di-alkylamino, hydroxyalkyl, alkoxyalkyl, benzyloxy,cycloalkylalkyl, cycloalkoxy, cycloalkylalkoxy, alkylsulfonyloxy,optionally substituted thienyl, optionally substituted pyrazolyl,optionally substituted pyridinyl, morpholinocarbonyl,—(CH₂)_(q)—S(O)_(r)R^(f); —(CH₂)_(q)—NR^(g)R^(h);—(CH₂)_(q)—C(═O)—NR^(g)R^(h); —(CH₂)_(q)—C(═O)—C(═O)NR^(g)R^(h);—(CH₂)_(q)—SO₂—NR^(g)R^(h); —(CH₂)_(q)—N(R^(f))—C(═O)—R^(i);—(CH₂)_(q)—C(═O)—R^(i); or —(CH₂)_(q)—N(R^(f))—SO₂—R^(g); where q is 0or 1, r is from 0 to 2, R^(f), R^(g), and R^(h) each independently ishydrogen or alkyl, and each R^(i) is independently hydrogen, alkyl,hydroxy, or alkoxy. Certain preferred optional substituents for “aryl”,phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” include alkyl,halo, haloalkyl, alkoxy, cyano, amino and alkylsulfonyl. More preferredsubstituents are methyl, fluoro, chloro, trifluoromethyl, methoxy andmethanesulfonyl.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

acid addition salts formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid,benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid,ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid,glutamic acid, glycolic acid, hydroxynaphtoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, muconic acid,2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinicacid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, andthe like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic or inorganicbase. Acceptable organic bases include diethanolamine, ethanolamine,N-methylglucamine, triethanolamine, tromethamine, and the like.Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like.Skilled persons will know how to choose a group for the ease of removaland for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Disease states” associated with serotonin and norepinephrineneurotransmission include depressive and anxiolytic disorders, as wellas schizophrenia and other psychoses, dyskinesias, drug addition,cognitive disorders, Alzheimer's disease, attention deficit disorderssuch as ADHD, obsessive-compulsive behaviour, panic attacks, socialphobias, eating disorders such as obesity, anorexia, bulimia and“binge-eating”, stress, hyperglycaemia, hyperlipidaemia,non-insulin-dependent diabetes, seizure disorders such as epilepsy, andtreatment of conditions associated with neurological damage resultingfrom stroke, brain trauma, cerebral ischaemia, head injury, haemorrhage,and disorders and disease states of the urinary tract.

“Depression” as used herein includes, but is not limited to, majordepression, long-term depression, dysthymia, mental states of depressedmood characterised by feelings of sadness, despair, discouragement,“blues”, melancholy, feelings of low self esteem, guilt and selfreproach, withdrawal from interpersonal contact, and somatic symptomssuch as eating and sleep disturbances.

“Anxiety” as used herein includes, but is not limited to, unpleasant orundesirable emotional states associated with psychophysiologicalresponses to anticipation of unreal, imagined or exaggerated danger orharm, and physical concomitants such as increased heart rate, alteredrespiration rate, sweating, trembling, weakness and fatigue, feelings ofimpending danger, powerlessness, apprehension and tension.

“Disorders of the urinary tract” or “uropathy” used interchangeably with“symptoms of the urinary tract” means the pathologic changes in theurinary tract. Examples of urinary tract disorders include, but are notlimited to, stress incontinence, urge incontence, benign prostatichypertrophy (BPH), prostatitis, detrusor hyperreflexia, outletobstruction, urinary frequency, nocturia, urinary urgency, overactivebladder, pelvic hypersensitivity, urethritis, prostatodynia, cystitis,idiophatic bladder hypersensitivity, and the like.

“Disease states associated with the urinary tract” or “urinary tractdisease states” or “uropathy” used interchangeably with “symptoms of theurinary tract” mean the pathologic changes in the urinary tract, ordysfunction of urinary bladder smooth muscle or its innervation causingdisordered urinary storage or voiding. Symptoms of the urinary tractinclude, but are not limited to, overactive bladder (also known asdetrusor hyperactivity), outlet obstruction, outlet insufficiency, andpelvic hypersensitivity.

“Overactive bladder” or “detrusor hyperactivity” includes, but is notlimited to, the changes symptomatically manifested as urgency,frequency, altered bladder capacity, incontinence, micturitionthreshold, unstable bladder contractions, sphincteric spasticity,detrusor hyperreflexia (neurogenic bladder), detrusor instability, andthe like.

“Outlet obstruction” includes, but is not limited to, benign prostatichypertrophy (BPH), urethral stricture disease, tumors, low flow rates,difficulty in initiating urination, urgency, suprapubic pain, and thelike.

“Outlet insufficiency” includes, but is not limited to, urethralhypermobility, intrinsic sphincteric deficiency, mixed incontinence,stress incontinence, and the like.

“Pelvic Hypersensitivity” includes, but is not limited to, pelvic pain,interstitial (cell) cystitis, prostatodynia, prostatitis, vulvadynia,urethritis, orchidalgia, overactive bladder, and the like.

“Pain” means the more or less localized sensation of discomfort,distress, or agony, resulting from the stimulation of specialized nerveendings. There are many types of pain, including, but not limited to,lightning pains, phantom pains, shooting pains, acute pain, inflammatorypain, neuropathic pain, complex regional pain, neuralgia, neuropathy,and the like (Dorland's Illustrated Medical Dictionary, 28^(th) Edition,W. B. Saunders Company, Philadelphia, Pa.). The goal of treatment ofpain is to reduce the degree of severity of pain perceived by atreatment subject.

“Neuropathic pain” means the pain resulting from functional disturbancesand /or pathological changes as well as noninflammatory lesions in theperipheral nervous system. Examples of neuropathic pain include, but arenot limited to, thermal or mechanical hyperalgesia, thermal ormechanical allodynia, diabetic pain, entrapment pain, and the like.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical        symptoms of the disease state not to develop in a subject that        may be exposed to or predisposed to the disease state, but does        not yet experience or display symptoms of the disease state.    -   (ii) inhibiting the disease state, i.e., arresting the        development of the disease state or its clinical symptoms, or    -   (iii) relieving the disease state, i.e., causing temporary or        permanent regression of the disease state or its clinical        symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixture

which ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. Chemical structures shownherein were prepared using ISIS® version 2.2. Any open valency appearingon a carbon, oxygen or nitrogen atom in the structures herein indicatesthe presence of a hydrogen atom.

Whenever a chiral carbon is present in a chemical structure, it isintended that all stereoisomers associated with that chiral carbon areencompassed by the structure.

All patents and publications identified herein are incorporated hereinby reference in their entirety.

Compounds of the Invention

The invention provides compounds of formula I:

wherein:

-   Ar is optionally substituted indolyl;-   R¹ is:

hydrogen; or

C₁₋₆alkyl; and

-   R² is:

hydrogen;

C₁₋₆alkyl;

C₁₋₆alkoxy;

halo;

halo-C₁₋₆alkyl;

hetero-C₁₋₆alkyl;

C₁₋₆alkylsulfonyl;

cyano;

amino;

C₁₋₆alkylamino;

di-C₁₋₆alkylamino;

heterocyclyl selected from piperazinyl, piperidinyl, pyrrolidinyl,morpholinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl,each optionally substituted;

heterocyclyl-C₁₋₆alkyl selected from piperazinyl-C₁₋₆alkyl,piperidinyl-C₁₋₆alkyl, pyrrolidinyl-C₁₋₆alkyl, morpholinyl-C₁₋₆alkyl,thiomorpholinyl-C₁₋₆alkyl, tetrahydropyranyl-C₁₋₆alkyl andtetrahydrofuranyl-C₁₋₆alkyl, the heterocyclyl portion of each optionallysubstituted;

—(CH₂)_(m)—C(O)—NR^(a)R^(b);

—(CH₂)_(m)—SO₂—NR^(a)R^(b);

—(CH₂)_(m)—C(O)—OR^(c);

—NR^(d)—C(O)—R^(e);

—NR^(d)—SO₂—R^(e);

—O—C(O)—R^(e);

—O—C(O)—NR^(a)R^(b);

—NR^(d)—C(O)—NR^(a)R^(b); or

—NR^(d)—C(O)—OR^(c);

-   -   wherein m is 0 or 1 and R^(a), R^(b), R^(c), R^(d) and R^(e)        each independently is hydrogen or C₁₋₆alkyl.

It is to be understood that the scope of this invention encompasses notonly the various isomers which may exist but also the various mixture ofisomers which may be formed. Furthermore, the scope of the presentinvention also encompasses solvates and salts of compounds of formula I.

In certain embodiments of formula I, Ar is optionally substitutedindol-5-yl.

In certain embodiments of formula I, R¹ is hydrogen.

In certain embodiments of formula I, R¹ is C₁₋₆alkyl.

In certain embodiments of formula I, R² is hydrogen.

In certain embodiments of formula I, the compounds may be of the formulaIa or Ib:

wherein Ar, R¹ and R² are as defined herein.

In certain embodiments of formula Ia or formula Ib, Ar is optionallysubstituted indol-5-yl.

In certain embodiments of formula Ia or formula Ib, R¹ is hydrogen.

In certain embodiments of formula Ia or formula Ib, R¹ is C₁₋₆alkyl.

In certain embodiments of formula Ia or formula Ib, R² is hydrogen.

In certain embodiments of formula Ia or formula Ib, Ar is optionallysubstituted indol-5-yl and R¹ is hydrogen.

In certain embodiments of formula Ia or formula Ib, Ar is optionallysubstituted indol-5-yl, R¹ is hydrogen and R² is hydrogen.

In certain embodiments of the invention, the subject compounds may be ofthe formula II:

wherein:

-   R³ is:

hydrogen;

C₁₋₆alkyl;

C₁₋₆alkoxy;

halo;

halo-C₁₋₆alkyl;

hetero-C₁₋₆alkyl;

C₁₋₆alkylsulfonyl; or

cyano;

-   R⁴ is:

hydrogen;

C₁₋₆alkyl;

halo;

halo-C₁₋₆alkyl;

hetero-C₁₋₆alkyl;

—C(O)—NR^(f)R^(g) wherein R^(f) and R^(g) each independently is hydrogenor C₁₋₆alkyl;

C₁₋₆alkylsulfonyl; or

cyano;

-   R⁵ is:

hydrogen; or

C₁₋₆alkyl; and

-   R¹ and R² are as defined herein.

In certain embodiments of the invention, the subject compounds may be ofthe formula IIa or IIb:

wherein R¹, R², R³, R⁴ and R⁵ are as defined herein.

In certain embodiments of formula II, formula IIa or formula IIb, R¹ ishydrogen.

In certain embodiments of formula II, formula IIa or formula IIb, R¹ isC₁₋₆alkyl.

In certain embodiments of formula II, formula IIa or formula IIb, R² ishydrogen.

In certain embodiments of formula II, formula IIa or formula IIb, R³ ishydrogen.

In certain embodiments of formula II, formula IIa or formula IIb, R⁴ ishydrogen.

In certain embodiments of formula formula II, IIa or formula IIb, R⁵ ishydrogen.

Where any of R¹, R², R³, R⁴, R⁵, R^(a), R^(b), R^(c), R^(d), R^(e),R^(f) or R^(g) herein are alkyl or contain an alkyl moiety, such alkylis preferably lower alkyl, i.e. C₁-C₆alkyl, and more preferablyC₁-C₄alkyl.

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparecompounds of the invention, wherein Ar and R² are as defined herein.

In step 1 of Scheme A, cinnamate compound a is coupled with arylboronate compound b using a Rhodium(I) catalyst such ashydroxy(1,5-cyclooctadiene)rhodium (I) dimer or other suitable catalyst,to provide an arylpropyl ester compound c. Compound a may be preparedfrom the corresponding benzaldehyde by reaction of the benzaldehyde withmethyl (triphenylphosphoranylidene)acetate. Aryl boronate compound b maycomprise, for example, an indolyl boranate, an indazolyl boronate, abenzofuranyl boronate, a benzothiophenyl boranate or other aryl orheteroaryl boronate, each of which may be optionally substituted asdefined herein.

Treatment of compound c in step 2 with reducing agent results inreduction of the nitrile group and cyclization to form benzazepinonecompound d. Various reducing agents are suitable for this selectivereduction, including sodium borohydride. The reaction of step 2 may becarried out in the presence of pinacol.

In step 3, the carbonyl group of benzazepinone compound d is reduced tomethylene to provide benzazapine compound e. This reaction may beachieved using lithium aluminum hydride under polar aprotic solventconditions. Compound e is a compoud of formula I in accordance with theinvention.

Many variations on the procedure of Scheme A are possible. The cyanocompound c may, for example, be reduced to a benzylamine compound (notshown) which is then subsequently cyclized. The amine group of compounde may be subsequently alkylated for embodiments of the invention whereR¹ is alkyl. The compound e may be resolved into enantiomers usingsuitable chromatographic techniques. Other variations will suggestthemselves to those skilled in the art upon review of this disclosure.

Specific details for producing compounds of the invention are describedin the Examples section below.

Utility

The compounds of the invention are usable for the treatment of diseasesor conditions associated with serotonin neurotransmission,norepinephrine neuortransmission and/or dopamine neurotransmission. Suchdiseases and conditions include depressive and anxiolytic disorders, aswell as schizophrenia and other psychoses, dyskinesias, drug addition,cognitive disorders, Alzheimer's disease, attention deficit disorderssuch as ADHD, obsessive-compulsive behaviour, panic attacks, socialphobias, eating disorders such as obesity, anorexia, bulimia and“binge-eating”, stress, hyperglycaemia, hyperlipidaemia,non-insulin-dependent diabetes, seizure disorders such as epilepsy, andtreatment of conditions associated with neurological damage resultingfrom stroke, brain trauma, cerebral ischaemia, head injury, andhaemorrhage.

The compounds of the invention are also usable for treatment ofdisorders and disease states of the urinary tract such as stressincontinence, urge incontinence, benign prostatic hypertrophy (BPH),prostatitis, detrusor hyperreflexia, outlet obstruction, urinaryfrequency, nocturia, urinary urgency, overactive bladder, pelvichypersensitivity, urethritis, prostatodynia, cystitis, idiophaticbladder hypersensitivity.

The compounds of the invention also possess anti-inflammatory and/oranalgesic properties in vivo, and accordingly, are expected to findutility in the treatment of disease states associated with painconditions from a wide variety of causes, including, but not limited to,neuropathic pain, inflammatory pain, surgical pain, visceral pain,dental pain, premenstrual pain, central pain, pain due to bums, migraineor cluster headaches, nerve injury, neuritis, neuralgias, poisoning,ischemic injury, interstitial cystitis, cancer pain, viral, parasitic orbacterial infection, post-traumatic injuries (including fractures andsports injuries), and pain associated with functional bowel disorderssuch as irritable bowel syndrome.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at leastone compound of the present invention, or an individual isomer, racemicor non-racemic mixture of isomers or a pharmaceutically acceptable saltor solvate thereof, together with at least one pharmaceuticallyacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

In general, the compounds of the invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

Compounds of the invention may be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation. The preferred manner of administration isgenerally oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the invention may be formulated in a wide variety oforal administration dosage forms. The pharmaceutical compositions anddosage forms may comprise a compound or compounds of the presentinvention or pharmaceutically acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets preferably contain fromabout one (1) to about seventy (70) percent of the active compound.Suitable carriers include but are not limited to magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

The compounds of the invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. Thesolutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette or spray. Theformulations may be provided in a single or multidose form. In thelatter case of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described below.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Unless otherwise stated, all temperatures including melting points(i.e., MP) are in degrees celsius (° C.). It should be appreciated thatthe reaction which produces the indicated and/or the desired product maynot necessarily result directly from the combination of two reagentswhich were initially added, i.e., there may be one or more intermediateswhich are produced in the mixture which ultimately leads to theformation of the indicated and/or the desired product. The followingabbreviations may be used in the Preparations and Examples.

Abbreviations

DCM dichloromethane/methylene chloride

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

ECDI 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide

EtOAc ethyl acetate

EtOH ethanol

gc gas chromatography

HMPA hexamethylphosphoramide

HOBt N-Hydroxybenzotriazole

hplc high performance liquid chromatography

mCPBA m-chloroperbenzoic acid

MeCN acetonitrile

NMP N-methyl pyrrolidinone

TEA triethylamine

THF tetrahydrofuran

LAH lithium aluminum hydride

LDA lithium diisopropylamine

TLC thin layer chromatography

Example 1

The synthetic procedure used in this example is outlined below in SchemeB.

Step 1 3-(2-Cyano-phenyl)-acrylic acid methyl ester

To a solution of 2-cyanobenzaldehyde (5.0 g, 38 mmol) in benzene (100mL) was added methyl (triphenylphosphoranylidene)acetate (14 g, 42mmol), and the resulting solution was heated to reflux for 15 hours. Thecrude material was concentrated under reduced pressure onto silica geland purified by flash chromatography (dichloromethane) to afford3-(2-Cyano-phenyl)-3-(1H-indol-5-yl)-propionic acid methyl ester as awhite solid (7.0 g). MS (M+H)=188.

Step 2 3-(2-Cyano-phenyl)-3-(1H-indol-5-yl)-propionic acid methyl ester

To a mixture of 3-(2-cyano-phenyl)-3-(1H-indol-5-yl)-propionic acidmethyl ester (3.0 g, 16 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)-1H-indole (5.8 g, 24mmol), and hydroxy(1,5-cyclooctadiene)rhodium (I) dimer (0.37 g, 0.80mmol) was added 6:1 dioxane:water (120 mL) and triethylamine (2.4 g, 24mmol). The reaction mixture was heated under nitrogen in a 90° C. oilbath for 90 minutes. The reaction mixture was cooled to roomtemperature, diluted with water (200 mL), and extracted with ethylacetate. The combined organic layer was dried over magnesium sulfate,filtered and concentrated to a dark green oil, which was purified byflash chromatography (ethyl acetate/hexane) to obtain pure3-(2-Cyano-phenyl)-3-(1H-indol-5-yl)-propionic acid methyl ester as apale yellow foam (2.7 g), as well as some product in a 1:2 molar ratiomixture with pinacol as a yellow-orange semisolid (2.1 g). MS (M+H)=305.

Step 3 5-(1H-Indol-5-yl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one

To a mixture of 3-(2-cyano-phenyl)-3-(1H-indol-5-yl)-propionic acidmethyl ester and pinacol (1:2 molar ratio, 2.1 g) in methanol (100 mL)was added sodium borohydride (2.6 g, 14 mmol), portionwise over 45minutes. Stirring continued for 15 hours at room temperature. Thereaction mixture was then filtered through Celite, washed with methanol,and the combined filtrates were concentrated. The crude material soobtained was partitioned between ethyl acetate and 5% aqueous ammoniumhydroxide. The organic layer was dried over sodium sulfate, filtered andconcentrated to a yellow oil which contained a mixture of5-(1H-Indol-5-yl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one and uncyclized3-(2-aminomethyl-phenyl)-3-(1H-indol-5-yl)-propionic acid methyl ester(not shown in Scheme B). This crude oil was suspended in 1,4-dioxane(100 mL) and heated to reflux for 40 hours, then cooled and concentratedto a brown oil and purified by flash chromatography (methanol/ethylacetate) to afford pure5-(1H-Indol-5-yl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one as a whitesolid (0.50 g). MS (M+H)=277.

Step 4 5-(1H-Indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine

To an ice-water bath cooled suspension of5-(1H-indol-5-yl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one (0.50 g, 1.8mmol) in tetrahydrofuran (75 mL) was added lithium aluminum hydride(0.27 g, 7.2 mmol) as a slurry in tetrahydrofuran (5 mL). The mixturewas heated to reflux for 100 minutes, then cooled in an ice-water bathand quenched with water (0.6 mL), 15% aqueous KOH (0.6 mL), and alsocrushed sodium sulfate decahydrate (14 g). The mixture was stirredmixture at room temperature for 30 minutes, then filtered and washedwith ethyl acetate. The organic layer was concentrated to a yellow oilthat was purified by flash chromatography (ammoniumhydroxide/methanol/dichloromethane) to afford pure5-(1H-indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a colorlessfoam (0.20 g, MS (M+H)=263), as well as some product (0.23 g)contaminated with an uncharacterized tetrahydrofuran-aluminum complex asa colorless foam. The contaminated product was dissolved in 1:1 ethylacetate:diethyl ether (5 mL), and 1.0 M HCl in diethyl ether (0.9 mL)was added dropwise, under a blanket of dry nitrogen gas. The white solidprecipitate was collected by filtration and washed with ice-cold diethylether and tetrahydrofuran. The solid was suspended in ethanol andevaporated to dryness under reduced pressure, and that process wasrepeated to afford pure5-(1H-indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine hydrochloride asan off-white powder (0.16 g).

Example 2 Resolution of5-(1H-Indol-5-yl)-2,3,4,5-tetrahydro-1H-benzorclazepine into(R)-5-(1H-Indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine and(S)-5-(1H-Indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine

A small sample of5-(1H-indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine 0.065 g) wasseparated into its enantiomers using preparative HPLC (Chiralpak IA,85:15 hexane:ethanol, 0.1% diethylamine) to provide 0.016 g of eachenantiomer as colorless foams.

Example 3 5-(1H-Indol-5-yl)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine

5-(1H-indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was subjected toreductive amination using formaldehyde and sodium triacetoxyborohydridein 1,2-dichloroethane to give5-(1H-indol-5-yl)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine as awhite powder in 50% yield.

Example 4 Formulations

Pharmaceutical preparations for delivery by various routes areformulated as shown in the following Tables. “Active ingredient” or“Active compound” as used in the Tables means one or more of theCompounds of Formula I.

Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration Ingredient Amount Active compound1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 gPropyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation Ingredient % wt./wt. Active ingredient 0.25 gSodium Chloride qs to make isotonic Water for injection 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation Ingredient % wt./wt. Active ingredient 1.0%Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Topical Formulation Ingredients grams Active compound 0.2-2 Span 60 2Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 5 Screening for Human Serotonin Transporter (hSERT) AntagonistsUsing a Scintillation Proximity Assay (SPA)

The screening assay of this example was used to determine the affinityof ligands at the hSERT transporter by competition with [³H]-Citalopram.

Scintillation Proximity Assay (SPA) works by bringing radioligand withinclose proximity to the bead's scintillant to stimulate light emission.In this assay, the receptor-containing membranes were pre-coupled to theSPA beads and the binding of the appropriate radioligand to thetransporter was measured. The light emission was proportional to theamount of bound radioligand. Unbound radioligand produced no signal as aresult of distant proximity to scintillant (lack of energy transfer).

HEK-293 cells (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258)stably expressing recombinant hSERT were maintained with media (DMEMhigh glucose with 10% FBS, 300 μg/ml G418 and 2 mM L-Glutamine) andincubated at 37° C. with 5% CO₂. Cells are released from culture flasksusing PBS for 1-2 minutes. The cells were subsequently centrifuged at1000 g's for 5 minutes and resuspended in PBS prior to being used in themembrane preparation.

Cell membranes were prepared using a membrane preparation buffer of 50mM TRIS (pH 7.4). Cell membranes were prepared from a single cube(7.5×10⁹ cells total). Cells were homogenized using a Polytron (settingmedium for a 4 second burst). The homogenate was then centrifuged at48,000×g for 15 minutes, the supernatant subsequently removed anddiscarded, and the pellet resuspended with fresh buffer. After a secondcentrifugation, the pellet was re-homogenized and brought to a finalvolume determined during the assay. Typically, membrane portions werealiquoted in 3mg/ml (w:v). and stored at −80° C.

For Scintillation Proximity Assay IC₅₀/K_(i) determination, 50 mMTris-HCl and 300 mM NaCl, (pH 7.4) buffers were utilized. Compounds ofthe invention were diluted from 10 mM to 0.1 nM FAC (10 point curves,whole log/half log dilutions) via a Beckman Biomek 2000 using a serialdilution protocol. The test compounds were then transferred (20 μl/well)and the [³H]-Citalopram radioligand was added at 50 μl/well. Membraneand beads were prepared to a ratio of 10 μg: 0.7 mg, with 0.7 mg PVT-WGAAmersham beads (Cat#RPQ0282V) added per well. 130 μl of the membrane:bead mixture was added to the assay plate. The mixtures were allowed tostand at room temperature for one hour, and were then counted on aPackard TopCount LCS, a generic Scintillation Proximity Assay countingprotocol settings (Energy Range: Low, Efficiency Mode: Normal, Region A:1.50-35.00, Region B: 1.50-256.00, Count Time (min.): 0.40, BackgroundSubtract: none, Half-Life Correction: no, Quench Indicator: tSIS,Platemap blank subtraction: No, Cross talk reduction: Off).

The % inhibition was calculated for each compound tested [(Compoundcounts per minute (CPM) at maximum concentration-Non-Specific CPM)/TotalCPM*100]. The concentration producing 50% inhibition (IC₅₀) wasdetermined using an iterative non-linear curve fitting technique withActivity Base/Xlfit using the following equation:

$y = {\frac{\max - \min}{1 + \left( {{IC}\; {50/x}} \right)^{n}} + \min}$

where max=total binding, min=non specific binding, x=concentration (M)of the tested compound and n=Hill slope. The inhibition dissociationconstant (Ki) of each compound was determined according to the method ofCheng-Prusoff and then converted into negative logarithm (pKi) of theKi.

Using the above procedure, compounds of the invention were found to haveaffinity for human serotonin transporter. For example,5-(1H-Indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepinee exhibited a pKiof approximately 6.9 using the above assay.

Example 6 Screening for Compounds Active at Human NorepinephrineTransporter (hNET) Using a Scintillation Proximity Assay (SPA)

This assay was used to determine the affinity of ligands for the hNETtransporter by competition with [³H]-Nisoxetine. As in the hSERT assayof the above example, receptor-containing membranes were pre-coupled tothe SPA beads and the binding of the appropriate radioligand to thetransporter was measured. The light emission was proportional to theamount of bound radioligand, with unbound radioligand producing nosignal.

HEK-293 cells (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258)stably expressing recombinant hNET (Clone: HEK-hNET #2) were maintainedwith media (DMEM hi glucose with 10% FBS, 300 μg/ml G418 and 2 mML-Glutamine) and incubated at 37° C. with 5% CO₂. Cells were releasedfrom culture flasks using PBS for 1-2 minutes. The cells weresubsequently centrifuged at 1000g's for 5 minutes and resuspended in PBSprior to being used in the membrane preparation.

Cell membranes were prepared using a membrane preparation buffer of 50mM TRIS (pH 7.4). Cell membranes were prepared from a single cube(7.5×10⁹ cells total). Cells were homogenized using a Polytron (settingmedium for a 4 second burst). The homogenate was then centrifuged at48,000×g for 15 minutes, the supernatant subsequently removed anddiscarded, and the pellet resuspended with fresh buffer. After a secondcentrifugation, the pellet was re-homogenized and brought to a finalvolume determined during the assay. Typically, membrane portions werealiquoted in 3-6 mg/ml (w:v). and stored at −80° C.

³[H] Nisoxetine radioligand (Amersham Cat. #TRK942 or Perkin Elmer Cat.#NET1084, specific activity: 70-87 Ci/mmol, stock concentration: 1.22e-5M, final concentration: 8.25e-9 M), and 50 mM Tris-HCl, 300 mM NaCl, (pH7.4) buffers were used for Scintillation Proximity Assay IC₅₀/K_(i)determination. Compounds of the invention were diluted from 10 mM to 0.1nM FAC (10 point curves, whole log/half log dilutions) via a BeckmanBiomek 2000 using a serial dilution protocol. The test compounds werethen transferred (20 μl/well) and the radioligand was added at 50μl/well. Membrane and beads were prepared to a ratio of 10 μg: 0.7 mg,with 0.7 mg PVT-WGA Amersham beads (Cat#RPQ0282V) added per well. 130 μlof the membrane: bead mixture was added to the assay plate. The mixtureswere allowed to stand at room temperature for one hour, and were thencounted on a Packard TopCount LCS, a generic SPA counting protocolsettings (Energy Range: Low, Efficiency Mode: Normal, Region A:1.50-35.00, Region B: 1.50-256.00, Count Time (min.): 0.40, BackgroundSubtract: none, Half-Life Correction: no, Quench Indicator: tSIS,Platemap blank subtraction: No, Cross talk reduction: Off).

The % inhibition was calculated for each compound tested [(Compound CPMat maximum concentration-Non-Specific CPM)/Total CPM*100]. Theconcentration producing 50% inhibition (IC₅₀) was determined using aniterative non-linear curve fitting technique with Activity Base/Xlfitusing the following equation:

$y = {\frac{\max - \min}{1 + \left( {{IC}\; {50/x}} \right)^{n}} + \min}$

where max=total binding, min=non specific binding, x=concentration (M)of the tested compound and n=Hill slope. The inhibition dissociationconstant (Ki) of each compound was determined according to the method ofCheng-Prusoff and then converted into negative logarithm (pKi) of theKi.

Using the above procedure, compounds of the invention were found to haveaffinity for the human norepinephrine transporter. For example,5-(1H-Indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine exhibited a pKiof approximately 8.0 using the above assay.

Example 7 Screening for Compounds Active at Human Dopamine TransporterUsing a Scintillation Proximity Assay (SPA)

This assay was used to determine the affinity of ligands for thedopamine transporter by competition with [³H]-Vanoxerine.

HEK-293 cells (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258)stably expressing recombinant hDAT were maintained with media (DMEM higlucose with 10% FBS, 300 μg/ml G418 and 2 mM L-Glutamine) and incubatedat 37° C. with 5% CO₂. Cells were plated four hours prior to experimentby placing approximately 30,000 cells per well (in PBS) on white, opaqueCell-Tak coated 96 well plates. Extra buffer was apriated from the cellplates using an ELx405 plate washer.

³[H] vanoxerine (GBR 12909) radioligand, specific activity approximately59 Ci/mmol, stock concentration, 400 nM, and 50 mM Tris-HCl, 300 mMNaCl, (pH 7.4) buffers were used for Scintillation Proximity AssayIC₅₀/K_(i) determination. Compounds of the invention were diluted from10 mM to 0.1 nM FAC (10 point curves, whole log/half log dilutions) viaa Beckman Biomek 2000 using a 10-point dilution protocol. The mixtureswere allowed to stand at room temperature for 30 minutes, and were thencounted on a Packard TopCount LCS, a generic SPA counting protocolsettings, Count Time (min.): 0.40, Background Subtract: none, Half-LifeCorrection: none, Quench Indicator: tSIS, Platemap blank subtraction:none, Cross talk reduction: Off).

The % inhibition was calculated for each compound tested [(Compound CPMat maximum concentration-Non-Specific CPM)/Total CPM*100]. Theconcentration producing 50% inhibition (IC₅₀) was determined using aniterative non-linear curve fitting technique with Activity Base/Xlfitusing the following equation:

$y = {\frac{\max - \min}{1 + \left( {{IC}\; {50/x}} \right)^{n}} + \min}$

where max=total binding, min=non specific binding, x=concentration (M)of the tested compound and n=Hill slope. The inhibition dissociationconstant (Ki) of each compound was determined according to the method ofCheng-Prusoff and then converted into negative logarithm (pKi) of theKi.

Using the above procedure, compounds of the invention were found to haveaffinity for the human dopamine transporter. For example,5-(1H-Indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine exhibited a pKiof approximately 8.7 using the above assay.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound of the formula I:

wherein: Ar is optionally substituted indolyl; R¹ is: hydrogen; orC₁₋₆alkyl; and R² is: hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy; halo;halo-C₁₋₆alkyl; hetero-C₁₋₆alkyl; C₁₋₆alkylsulfonyl; cyano; amino;C₁₋₆alkylamino; di-C₁₋₆alkylamino; heterocyclyl selected frompiperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl and tetrahydrofuranyl, each optionally substituted;heterocyclyl-C₁₋₆alkyl selected from piperazinyl-C₁₋₆alkyl,piperidinyl-C₁₋₆alkyl, pyrrolidinyl-C₁₋₆alkyl, morpholinyl-C₁₋₆alkyl,thiomorpholinyl-C₁₋₆alkyl, tetrahydropyranyl-C₁₋₆alkyl andtetrahydrofuranyl-C₁₋₆alkyl, the heterocyclyl portion of each optionallysubstituted; —(CH₂)_(m)—C(O)—NR^(a)R^(b); —(CH₂)_(m)—SO₂—NR^(a)R^(b);—(CH₂)_(m)—C(O)—OR^(c); —NR^(d)—C(O)—R^(e); —NR^(d)SO₂—R^(e);—O—C(O)—R^(e); —O—C(O)—NR R^(b); —NR^(d)—C(O)—NR^(a)R^(b); or—NR^(d)C(O)—OR^(c); wherein m is 0 or 1 and R^(a), R^(b), R^(c), R^(d)and R^(e) each independently is hydrogen or C₁₋₆alkyl.
 2. The compoundof claim 1, wherein Ar is optionally substituted indol-5-yl.
 3. Thecompound of claim 2, wherein R¹ is hydrogen.
 4. The compound of claim 3,wherein R² is hydrogen
 5. The compound of claim 3, wherein R² is halo.6. The compound of claim 1, wherein said compound is of the formula Iaor Ib:

wherein Ar, R¹ and R² are as recited in claim
 1. 7. The compound ofclaim 4, wherein Ar is optionally substituted indol-5-yl.
 8. Thecompound of claim 7, wherein R¹ is hydrogen.
 9. The compound of claim 1,wherein said compound is of the formula IIa or IIb:

wherein: R³ is: hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy; halo; halo-C₁₋₆alkyl;hetero-C₁₋₆alkyl; C₁₋₆alkylsulfonyl; or cyano; R⁴ is: hydrogen;C₁₋₆alkyl; halo; halo-C₁₋₆alkyl; hetero-C₁₋₆alkyl; —C(O)—NR^(a)R^(b)wherein R^(a) and R^(b) each independently is hydrogen or C₁₋₆alkyl;C₁₋₆alkylsulfonyl; or cyano; R⁵ is: hydrogen; or C₁₋₆alkyl; and R¹ andR² are as recited in claim
 1. 10. The compound of claim 9, wherein thecompound is of formula IIa.
 11. The compound of claim 10, wherein R¹ ishydrogen.
 12. The compound of claim 11, wherein R² is hydrogen.
 13. Thecompound of claim 12, wherein R³ is hydrogen.
 14. The compound of claim13, wherein R⁴ is hydrogen.
 15. The compound of claim 14, wherein R⁴ ishydrogen.
 16. A pharmaceutical composition comprising a compound ofclaim 1 and a pharmaceutically acceptable carrier.
 17. A method fortreating depression, anxienty, or a combination thereof mediated byserotonin or norepinephrine neurotransmission or a combination thereof,said method comprising administering to a subject in need thereof aneffective amount of a compound of claim 1